Non-genomic mechanisms of protein phosphatase 2A (PP2A) regulation in cancer

Abstract

Propagation of transient signals requires coordinated suppression of antagonistic phosphatase activity. Protein phosphatase 2A (PP2A) is a broad specificity serine/threonine phosphatase that functions as an antagonist of many signaling pathways associated with growth and proliferation, and endogenous inhibitory mechanisms suppress PP2A activity in response to mitogenic stimuli. These inhibitory mechanisms, including expression and activation of endogenous inhibitor proteins and phosphoregulation of PP2A subunits, are also engaged by aberrant constitutive activation of mitogenic pathways in cancer.

Inhibition of PP2A activity has been shown to promote malignant transformation and endogenous inhibitory mechanisms of PP2A have been associated with malignant progression and prognosis in a wide range of cancers. Despite existence of recurrent mutations and other genetic and gene regulatory alterationsin PP2A genes, they collectively appear at relatively low frequency, and in only some cancer types. The non-genomic inhibition of PP2A activity by increased expression of endogenous PP2A inhibitor proteins greatly exceeds the frequency of genetic mutations of PP2A genes in human cancers. This feature makes PP2A an untypical tumor suppressor, and may have influenced its recognition as one of the critical human cell transformation mechanisms.

We propose that non-genetic inhibition is the dominant mechanism causing loss of PP2A tumor suppressor function in cancer cells, possibly because these mechanisms do not elicit genomic instability associated with genetic loss of function of specific PP2A subunits.

Introduction

Phosphorylation-dependent signal transduction requires coordinated regulation of kinases and phosphatases (Hunter, 1995). The importance of duration and amplitude of kinase activities (Kolch et al., 2015; Rauch et al., 2016), as well as transient inhibition of phosphatase activities for efficient signal propagation (Braconi Quintaje et al., 1996b; Hornberg et al., 2005; Kolch et al., 2015) is well established. However, the endogenous mechanism by which phosphatase activities are regulated to ensure proper signal propagation are as yet poorly understood.

In this review, we discuss the non-genetic mechanisms that regulate dephosphorylation activity of a major human serine-threonine phosphatase protein phosphatase 2A (PP2A) in cancer cells. We specifically emphasize those endogenous mechanisms, which play a role in physiological phosphorylation regulation, but which are also engaged by the aberrant constitutive activation of oncogenic signalling pathways. PP2A functions as a protein complex consisting of a core trimer between the scaffolding A subunit (PPP2R1A, PPP2R1B), the catalytic subunit PP2AC (PPP2CA, PPP2CB), and one of the regulatory B subunits that are divided to three structurally distinct subfamilies (reviewed comprehensively in (Eichhorn et al., 2009; Meeusen and Janssens, 2017; Westermarck and Hahn, 2008)) (Fig. 1). Different combinations of A, B and catalytic subunits give rise to large number of distinct trimers, and the PP2A complexes, together with another phosphatase PP1, make up the vast majority of all serine/threonine targeted dephosphorylation activity (Cohen, 1989; Eichhorn et al., 2009). Although different B-subunits have partly redundant functions, each trimer may have their specific physiological activity due to cell type and tissue restricted expression of some subunits, differences in subcellular localization, as well as selective protein interactions between different B-subunits and their target proteins. Thereby, even though PP2A in general is an abundant broad specificity serine/threonine phosphatase, only some of the B-subunit containing PP2A complexes have been implicated in tumor suppression due to their functions as antagonists of oncogenic signalling pathways (Eichhorn et al., 2009; Meeusen and Janssens, 2017; Sablina et al., 2010; Westermarck and Hahn, 2008) (Fig. 1). Well known examples of B-subunits and their identified targets relevant for tumor suppression are PPP2R5A (B56α)-mediated regulation of serine 62 phosphorylated MYC (Myant et al., 2015; Yeh et al., 2004), and PPP2R2A (B55α) or PPP2R5C (B56γ)-mediated negative regulation of AKT kinase phosphorylation (Eichhorn et al., 2009; Meeusen and Janssens, 2017; Sablina et al., 2010). The functional relevance of these targets in PP2A mediated tumor suppression is evidenced by transformation of several types of human cells where the transforming effect of PP2A inhibition (Westermarck and Hahn, 2008) can be substituted by activation of MAPK, c-MYC, Wnt, and/or PI3K signalling (Sablina et al., 2010; Sontag et al., 1993; Tan et al., 2010; Yeh et al., 2004; Zhao et al., 2003) (Fig. 1). Notably, PP2A also has an emerging role in the regulation of senescence and p53-mediated tumor suppression (Laine et al., 2013; Mannava et al., 2012; Nobumori et al., 2013; Ruediger et al., 2011; Sotillo et al., 2008) (Fig. 1), a finding that is likely to have been overlooked in the transformation experiments relying on constitutive suppression of p53 and RB1.

Lastly, PP2A engages in complex negative feedback regulation with proliferation associated oncogenic pathways. In this review we discuss, using MAPK and JAK/STAT signalling as examples, how proliferation associated signalling contributes to PP2A inhibition in cancer cells.